The Th1/Th2 paradigm has provided the framework for understanding CD4+ T-cell biology and the interplay between innate and adaptive immunity for almost two decades. The adaptive immune responses are vital for the eradication of infectious agents, although dysregulated adaptive immune responses might also lead to autoimmune and chronic inflammatory diseases. A principal component of the adaptive immune response is the CD4+ T cell, which can orchestrate the functional activity of both innate and adaptive immune systems. The directed differentiation of effector CD4+ T cells by cytokines produced by pathogen-activated cells of the innate immune system provides a mechanism to coordinate the innate and adaptive immune responses for greatest host protection. Classically, effector CD4+ T cells have been divided into two distinct lineages on the basis of their cytokine production profile: cells of the T helper (Th)1 lineage, which evolved to enhance eradication of intracellular pathogens (e.g. intracellular bacteria, viruses and some protozoa), are characterized by their production of interferon gamma (IFN-γ), a potent activator of cell-mediated immunity; and cells of the Th2 lineage, which evolved to enhance elimination of parasitic infections (e.g. helminths), are characterized by production of interleukin (IL)-4, IL-5, and IL-13, which are potent activators of B-cell immunoglobulin (Ig)E production, eosinophil recruitment and mucosal expulsion mechanisms (mucous production and hypermotility). Immune pathogenesis that results from dysregulated Th1 responses to self or commensal floral antigens can promote tissue destruction and chronic inflammation, whereas dysregulated Th2 responses can cause allergy and asthma.
Recent studies have defined a previously unknown arm of the CD4+ T cell effector response, referred to as Th-17 cells, which is involved in immune regulation, immune pathogenesis and host defense. This knowledge has forced a reassessment of the Th1 lineage in autoimmunity and chronic inflammatory diseases. The cytokines IL-23 and IL-17, produced by Th-17 cells, have been linked to immune pathogenesis previously attributed to the Th1 lineage. However, the factors that specify differentiation of IL-17 effector cells from CD4+ T-cell precursors are not understood. As a result, methods of treatment and prevention aimed at modulating the Th-17 developmental pathway and compositions for use in such methods have not been appreciated.
The present disclosure describes the development pathway of Th-17 cells, thereby offering novel insights on mechanisms to prevent and/or treat disease states and conditions associated with Th-17 function (either increased or decreased).